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The apolipoprotein E gene affects the three-year trajectories of compensatory neural processes in the left-lateralized hippocampal network

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Abstract

Previous cross-sectional studies that investigated the effects of apolipoprotein E (ApoE) ε4 status on hippocampal networks have shown inconsistent results. Aging is a well-known risk factor for Alzheimer’s disease (AD) and could strongly interact with ApoE-related vulnerabilities to affect AD risk. However, no longitudinal data have been published regarding the interaction of the ApoE genotype and aging on hippocampal networks. Fifty-one patients with amnestic-type mild cognitive impairment (aMCI) and 64 matched cognitively normal elderly subjects underwent resting-state fMRI scans and neuropsychological tests at baseline and at a 35-month follow-up. Hippocampal resting-state functional connectivity (FC) data were analyzed utilizing a mixed analysis of covariance with ApoE genotype, time points and disease as fixed factors, controlling for age, sex and years of education. The notable finding was that the FC between the left hippocampus and right frontal regions for ε4 carriers longitudinally increased in the normal subjects, but decreased in aMCI patients, whereas the FC for non-carriers was maintained in normal subjects but increased in aMCI patients. Specifically, the longitudinal increases in hippocampal FC with the right inferior frontal gyrus were positively correlated with the changes in episodic memory test scores in non-carriers with aMCI. The interaction between the ApoE genotype, aging and disease suggested that aging should be considered a key regulator of the impact of the ApoE genotype on the phenotypic variants of AD. These findings also demonstrated that compensatory neural processes were accelerated in genetically high risk individuals, but could be subsequently exhausted with the onset of cognitive impairment.

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References

  • Apostolova, L. G., Dutton, R. A., Dinov, I. D., Hayashi, K. M., Toga, A. W., Cummings, J. L., et al. (2006). Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Archives of Neurology, 63(5), 693–699. doi:10.1001/archneur.63.5.693.

    Article  PubMed  Google Scholar 

  • Bai, F., Zhang, Z., Watson, D. R., Yu, H., Shi, Y., Yuan, Y., et al. (2009). Abnormal functional connectivity of hippocampus during episodic memory retrieval processing network in amnestic mild cognitive impairment. Biological Psychiatry, 65(11), 951–958. doi:10.1016/j.biopsych.2008.

    Article  PubMed  Google Scholar 

  • Bai, F., Xie, C., Watson, D. R., Shi, Y., Yuan, Y., Wang, Y., et al. (2011). Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study. PloS One, 6(12), e29288. doi:10.1371/journal.pone.0029288PONE-D-11-21110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bakker, A., Krauss, G. L., Albert, M. S., Speck, C. L., Jones, L. R., Stark, C. E., et al. (2012). Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron, 74(3), 467–474. doi:10.1016/j.neuron.2012.03.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., et al. (2011). Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Science Translational Medicine, 3(89), 89ra57. doi:10.1126/scitranslmed.3002156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chuang, W. L., Hsieh, Y. C., Wang, C. Y., Kuo, H. C., & Huang, C. C. (2010). Association of apolipoproteins e4 and c1 with onset age and memory: a study of sporadic Alzheimer disease in Taiwan. Journal of Geriatric Psychiatry and Neurology, 23(1), 42–48. doi:10.1177/0891988709351804.

    Article  PubMed  Google Scholar 

  • Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921–923.

    Article  CAS  PubMed  Google Scholar 

  • Damoiseaux, J. S., Beckmann, C. F., Arigita, E. J., Barkhof, F., Scheltens, P., Stam, C. J., et al. (2008). Reduced resting-state brain activity in the “default network” in normal aging. Cerebral Cortex, 18(8), 1856–1864. doi:10.1093/cercor/bhm207.

    Article  CAS  PubMed  Google Scholar 

  • Duverne, S., Motamedinia, S., & Rugg, M. D. (2009). The relationship between aging, performance, and the neural correlates of successful memory encoding. Cerebral Cortex, 19(3), 733–744. doi:10.1093/cercor/bhn122 bhn122.

    Article  PubMed  Google Scholar 

  • Grady, C. L., McIntosh, A. R., Beig, S., Keightley, M. L., Burian, H., & Black, S. E. (2003). Evidence from functional neuroimaging of a compensatory prefrontal network in Alzheimer’s disease. The Journal of Neuroscience, 23(3), 986–993.

    CAS  PubMed  Google Scholar 

  • Guo, C. C., Kurth, F., Zhou, J., Mayer, E. A., Eickhoff, S. B., Kramer, J. H., et al. (2012). One-year test-retest reliability of intrinsic connectivity network fMRI in older adults. NeuroImage, 61(4), 1471–1483. doi:10.1016/j.neuroimage.2012.03.027.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hahamy, A., Calhoun, V., Pearlson, G., Harel, M., Stern, N., Attar, F., et al. (2014). Save the global: global signal connectivity as a tool for studying clinical populations with functional magnetic resonance imaging. Brain Connectivity, 4(6), 395–403. doi:10.1089/brain.2014.0244.

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang, C. C., Hsieh, W. J., Lee, P. L., Peng, L. N., Liu, L. K., Lee, W. J., et al. (2015). Age-related changes in resting-state networks of a large sample size of healthy elderly. CNS Neuroscience & Therapeutics, 21(10), 817–825. doi:10.1111/cns.12396.

    Article  Google Scholar 

  • Kantarci, K., Lowe, V., Przybelski, S. A., Weigand, S. D., Senjem, M. L., Ivnik, R. J., et al. (2012). APOE modifies the association between Abeta load and cognition in cognitively normal older adults. Neurology, 78(4), 232–240. doi:10.1212/WNL.0b013e31824365ab.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laroche, S., Davis, S., & Jay, T. M. (2000). Plasticity at hippocampal to prefrontal cortex synapses: dual roles in working memory and consolidation. Hippocampus, 10(4), 438–446. doi:10.1002/1098-1063(2000)10:4<438::AID-HIPO10>3.0.CO;2-3.

    Article  CAS  PubMed  Google Scholar 

  • Lavenex, P., & Amaral, D. G. (2000). Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus, 10(4), 420–430. doi:10.1002/1098-1063(2000)10:4<420::AID-HIPO8>3.0.CO;2-5.

    Article  CAS  PubMed  Google Scholar 

  • Leshikar, E. D., Gutchess, A. H., Hebrank, A. C., Sutton, B. P., & Park, D. C. (2010). The impact of increased relational encoding demands on frontal and hippocampal function in older adults. Cortex, 46(4), 507–521. doi:10.1016/j.cortex.2009.07.011.

    Article  PubMed  Google Scholar 

  • Li, W., Antuono, P. G., Xie, C., Chen, G., Jones, J. L., Ward, B. D., et al. (2014). Aberrant functional connectivity in Papez circuit correlates with memory performance in cognitively intact middle-aged APOE4 carriers. Cortex, 57, 167–176. doi:10.1016/j.cortex.2014.04.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matura, S., Prvulovic, D., Hartmann, D., Scheibe, M., Sepanski, B., Butz, M., et al. (2016). Age-related effects of the apolipoprotein E gene on brain function. Journal of Alzheimer's Disease. doi:10.3233/JAD-150990.

    PubMed  Google Scholar 

  • Miller, S. L., Fenstermacher, E., Bates, J., Blacker, D., Sperling, R. A., & Dickerson, B. C. (2008). Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline. Journal of Neurology, Neurosurgery, and Psychiatry, 79(6), 630–635. doi:10.1136/jnnp.2007.124149.

    Article  CAS  PubMed  Google Scholar 

  • Morcom, A. M., Good, C. D., Frackowiak, R. S., & Rugg, M. D. (2003). Age effects on the neural correlates of successful memory encoding. Brain, 126(Pt 1), 213–229.

    Article  PubMed  Google Scholar 

  • Mori, E., Lee, K., Yasuda, M., Hashimoto, M., Kazui, H., Hirono, N., et al. (2002). Accelerated hippocampal atrophy in Alzheimer’s disease with apolipoprotein E epsilon4 allele. Annals of Neurology, 51(2), 209–214. doi:10.1002/ana.10093.

    Article  CAS  PubMed  Google Scholar 

  • Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., et al. (2010). APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Annals of Neurology, 67(1), 122–131. doi:10.1002/ana.21843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nyberg, L. (2016). Functional brain imaging of episodic memory decline in ageing. Journal of Internal Medicine. doi:10.1111/joim.12533.

    PubMed  Google Scholar 

  • Nyberg, L., Persson, J., Habib, R., Tulving, E., McIntosh, A. R., Cabeza, R., et al. (2000). Large scale neurocognitive networks underlying episodic memory. Journal of Cognitive Neuroscience, 12(1), 163–173.

    Article  CAS  PubMed  Google Scholar 

  • O’Brien, J. L., O’Keefe, K. M., LaViolette, P. S., DeLuca, A. N., Blacker, D., Dickerson, B. C., et al. (2010). Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology, 74(24), 1969–1976. doi:10.1212/WNL.0b013e3181e3966e.

    Article  PubMed  PubMed Central  Google Scholar 

  • Obler, L. K., Rykhlevskaia, E., Schnyer, D., Clark-Cotton, M. R., Spiro, A., Hyun, J., et al. (2010). Bilateral brain regions associated with naming in older adults. Brain and Language, 113(3), 113–123. doi:10.1016/j.bandl.2010.03.001.

    Article  PubMed  PubMed Central  Google Scholar 

  • Park, D. C., & Reuter-Lorenz, P. (2009). The adaptive brain: aging and neurocognitive scaffolding. Annual Review of Psychology, 60, 173–196. doi:10.1146/annurev.psych.59.103006.093656.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pennanen, C., Kivipelto, M., Tuomainen, S., Hartikainen, P., Hanninen, T., Laakso, M. P., et al. (2004). Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiology of Aging, 25(3), 303–310. doi:10.1016/S0197-4580(03)00084-8.

    Article  PubMed  Google Scholar 

  • Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256(3), 183–194. doi:10.1111/j.1365-2796.2004.01388.x.

    Article  CAS  PubMed  Google Scholar 

  • Pievani, M., Galluzzi, S., Thompson, P. M., Rasser, P. E., Bonetti, M., & Frisoni, G. B. (2011). APOE4 is associated with greater atrophy of the hippocampal formation in Alzheimer’s disease. NeuroImage, 55(3), 909–919. doi:10.1016/j.neuroimage.2010.12.081.

    Article  CAS  PubMed  Google Scholar 

  • Preston, A. R., & Eichenbaum, H. (2013). Interplay of hippocampus and prefrontal cortex in memory. Current Biology, 23(17), R764–R773. doi:10.1016/j.cub.2013.05.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Protas, H. D., Chen, K., Langbaum, J. B., Fleisher, A. S., Alexander, G. E., Lee, W., et al. (2013). Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurology, 70(3), 320–325. doi:10.1001/2013.jamaneurol.286.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rao, S. M., Bonner-Jackson, A., Nielson, K. A., Seidenberg, M., Smith, J. C., Woodard, J. L., et al. (2015). Genetic risk for Alzheimer’s disease alters the five-year trajectory of semantic memory activation in cognitively intact elders. NeuroImage, 111, 136–146. doi:10.1016/j.neuroimage.2015.02.011.

    Article  PubMed  PubMed Central  Google Scholar 

  • Reiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., et al. (2009). Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 106(16), 6820–6825. doi:10.1073/pnas.0900345106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reinvang, I., Espeseth, T., & Westlye, L. T. (2013). APOE-related biomarker profiles in non-pathological aging and early phases of Alzheimer’s disease. Neuroscience and Biobehavioral Reviews, 37(8), 1322–1335. doi:10.1016/j.neubiorev.2013.05.006.

    Article  CAS  PubMed  Google Scholar 

  • Reuter-Lorenz, P. A., & Park, D. C. (2014). How does it STAC up? Revisiting the scaffolding theory of aging and cognition. Neuropsychology Review, 24(3), 355–370. doi:10.1007/s11065-014-9270-9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016a). Age, APOE and Sex: triad of risk of Alzheimer’s disease. The Journal of Steroid Biochemistry and Molecular Biology. doi:10.1016/j.jsbmb.2016.03.012.

    PubMed  PubMed Central  Google Scholar 

  • Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016b). Age, APOE and sex: triad of risk of Alzheimer’s disease. The Journal of Steroid Biochemistry and Molecular Biology, 160, 134–147. doi:10.1016/j.jsbmb.2016.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rowe, C. C., Ellis, K. A., Rimajova, M., Bourgeat, P., Pike, K. E., Jones, G., et al. (2010). Amyloid imaging results from the Australian imaging, biomarkers and lifestyle (AIBL) study of aging. Neurobiology of Aging, 31(8), 1275–1283. doi:10.1016/j.neurobiolaging.2010.04.007.

    Article  PubMed  Google Scholar 

  • Saykin, A. J., Flashman, L. A., Frutiger, S. A., Johnson, S. C., Mamourian, A. C., Moritz, C. H., et al. (1999). Neuroanatomic substrates of semantic memory impairment in Alzheimer’s disease: patterns of functional MRI activation. Journal of the International Neuropsychological Society, 5(5), 377–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shu, H., Shi, Y., Chen, G., Wang, Z., Liu, D., Yue, C., et al. (2014a). Opposite neural trajectories of apolipoprotein E 4 and 2 Alleles with aging associated with different risks of Alzheimer’s disease. Cerebral Cortex. doi:10.1093/cercor/bhu237.

    PubMed Central  Google Scholar 

  • Shu, H., Yuan, Y., Xie, C., Bai, F., You, J., Li, L., et al. (2014b). Imbalanced hippocampal functional networks associated with remitted geriatric depression and apolipoprotein E epsilon4 allele in nondemented elderly: a preliminary study. Journal of Affective Disorders, 164, 5–13. doi:10.1016/j.jad.2014.03.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohn, W. S., Yoo, K., Na, D. L., & Jeong, Y. (2014). Progressive changes in hippocampal resting-state connectivity across cognitive impairment: a cross-sectional study from normal to Alzheimer disease. Alzheimer Disease and Associated Disorders, 28(3), 239–246. doi:10.1097/WAD.0000000000000027.

    Article  PubMed  Google Scholar 

  • Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., et al. (1993). Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 90(5), 1977–1981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, L., Zang, Y., He, Y., Liang, M., Zhang, X., Tian, L., et al. (2006). Changes in hippocampal connectivity in the early stages of Alzheimer’s disease: evidence from resting state fMRI. NeuroImage, 31(2), 496–504. doi:10.1016/j.neuroimage.2005.12.033.

    Article  PubMed  Google Scholar 

  • Wang, Z., Liang, P., Jia, X., Jin, G., Song, H., Han, Y., et al. (2012). The baseline and longitudinal changes of PCC connectivity in mild cognitive impairment: a combined structure and resting-state fMRI study. PloS One, 7(5), e36838. doi:10.1371/journal.pone.0036838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, X., Wang, J., He, Y., Li, H., Yuan, H., Evans, A., et al. (2015). Apolipoprotein E epsilon4 modulates cognitive profiles, hippocampal volume, and resting-state functional connectivity in Alzheimer’s disease. Journal of Alzheimer's Disease, 45(3), 781–795. doi:10.3233/JAD-142556.

    CAS  PubMed  Google Scholar 

  • Wierenga, C. E., Benjamin, M., Gopinath, K., Perlstein, W. M., Leonard, C. M., Rothi, L. J., et al. (2008). Age-related changes in word retrieval: role of bilateral frontal and subcortical networks. Neurobiology of Aging, 29(3), 436–451. doi:10.1016/j.neurobiolaging.2006.10.024.

    Article  PubMed  Google Scholar 

  • Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund, L. O., et al. (2004). Mild cognitive impairment--beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment. Journal of Internal Medicine, 256(3), 240–246. doi:10.1111/j.1365-2796.2004.01380.x.

    Article  CAS  PubMed  Google Scholar 

  • Yan, F. X., Wu, C. W., Chao, Y. P., Chen, C. J., & Tseng, Y. C. (2015). APOE-epsilon4 allele altered the rest-stimulus interactions in healthy middle-aged adults. PloS One, 10(6), e0128442. doi:10.1371/journal.pone.0128442.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zamboni, G., Wilcock, G. K., Douaud, G., Drazich, E., McCulloch, E., Filippini, N., et al. (2013). Resting functional connectivity reveals residual functional activity in Alzheimer’s disease. Biological Psychiatry, 74(5), 375–383. doi:10.1016/j.biopsych.2013.04.015.

    Article  PubMed  Google Scholar 

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Acknowledgments

This research was partly supported by the National Natural Science Foundation of China (No. 91332104, 81201080); Natural Science Foundation of Jiangsu Province (No. BK20160071); Six talent peaks project in Jiangsu Province (No. 2015-WSN-003); National High-tech R.D Program (863 Program) (No.2015AA020508); Key Program for Clinical Medicine and Science and Tochnology: Jiangsu Provence Clinical Medical Research Center (No.BL2013025); Program for New Century Excellent Talents in University (No. NCET-13-0117).

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  1. Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Qing Ye, Fan Su, Hao Shu, Liang Gong, Chunming Xie, Zhijun Zhang & Feng Bai

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  1. Qing Ye
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  2. Fan Su
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Ye, Q., Su, F., Shu, H. et al. The apolipoprotein E gene affects the three-year trajectories of compensatory neural processes in the left-lateralized hippocampal network. Brain Imaging and Behavior 11, 1446–1458 (2017). https://doi.org/10.1007/s11682-016-9623-5

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